A genetic clue to a mysterious disorder

Nature Genetics

October 18, 2016

The genetic basis of a painful and difficult-to-diagnose disorder is reported in a paper published online this week in Nature Genetics.

Ehlers-Danlos syndrome type III (EDS) is a collection of different disorders characterized by hypermobile joints and multiple unexplained symptoms, such as headache and body pain, skin flushing, severe itching and gastrointestinal problems. These varied and seemingly unrelated symptoms tend to be attributed to psychological or other factors because an underlying relationship between the symptoms has not been established.

Joshua Milner and colleagues recruited 96 individuals from 35 families in the United States with an inherited syndrome consistent with EDS. The patients also had elevated levels of tryptase - a protein produced as part of the immune response - but showed no other signs of immune cell dysfunction. Using genetic mapping methods and a test to look at gene copy numbers, the authors found that all of the families carried extra copies of a gene (TPSAB1) that produces one of the two types of tryptase, called alpha-tryptase. The number of copies of TPSAB1 was correlated with the severity of the symptoms.

The authors then looked at large databases of US patient records and found that, in every case where a patient had elevated serum tryptase levels, the patient also had extra copies of TPSAB1 but had not been diagnosed with EDS or immune cell disease. When the authors interviewed these people, they found that they had symptoms similar to those of the patients in the original study.

These findings may improve the diagnosis of patients with EDS-like symptoms who also have a family history of similar disease and elevated tryptase levels. The authors suggest that future research could explore treatments targeting alpha-tryptase, as complete loss of alpha-tryptase is common and does not cause any known clinical problems.